COngenital Diarrhea and Enteropathy (PediCODE) Consortium and BioRepository

PROJECT SUMMARY/ABSTRACT: This grant application aims to develop the PediCODE Consortium and Biorepository and identify the monogenic causes of Congenital Diarrhea and Enteropathy (CoDE). The CoDE disorders are rare monogenic disorders that are under-researched and associated with enormous management costs and adverse life-long outcomes. We will characterize these disorders' clinical and pathophysiological features and expand our clinical database and biorepository of disease-specific cells, tissues, and other primary patient materials. We anticipate that through these efforts, we will identify novel genes implicated in CoDE while we establish a unique resource enabling mechanistic studies on both known and unknown causal CoDE genes. To achieve these goals, we have assembled a multidisciplinary group of Physician-Scientists with an interest and experience in cell biology and genetic disorders resulting in diarrhea. The proposed research project aims to expand the clinical and sample repository that we have developed for studying CoDE disorders. Our initial aim focuses on enrolling CoDE patients into a multi-center cohort and capturing detailed clinical, genetic, and pathological data. Additionally, patient-derived samples will be collected to develop protein-interactome and single-cell transcriptomic data. Computational and image data tools will be developed to analyze these biopsies' enteroids and uncover features associated with each CoDE disorder. We will then address clinical cases where a causative variant in a known CoDE gene is not identified. A systematic pipeline, including whole exome and RNA sequencing, will be employed to identify and functionally validate unknown cases. Novel intestinal epithelial assays and patient-derived enteroids will provide a cellular phenotype of these disorders and be selectively supported with animal models. Finally, we will explore various options to examine therapeutic discovery for known CoDE disorders. We have developed quantitative assays of epithelial function in patient-derived enteroids, and animal models have been developed and validated. These assays will be adapted and extended for high-throughput applications in therapy development. Targeted screening for potential therapeutic modalities will be conducted, and pre-clinical validation will be performed using CoDE mouse and zebrafish models. The aim is to explore novel treatment principles in multiple models for clinical translation. The research project aims to expand the understanding of CoDE disorders, develop new tools and resources, identify and functionally study novel cases, and enable therapeutic discovery of known CoDE disorders. We anticipate that the PediCoDE Consortium and Biorepository will be a rich resource for patients, their families, clinicians, and scientific researchers. We anticipate that these efforts will expand our understanding of CoDE disorders and identify novel approaches for improving the clinical symptoms of affected children.